WO2012147619A1 - Inhibiteur d'augmentation du niveau de glycémie - Google Patents

Inhibiteur d'augmentation du niveau de glycémie Download PDF

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Publication number
WO2012147619A1
WO2012147619A1 PCT/JP2012/060610 JP2012060610W WO2012147619A1 WO 2012147619 A1 WO2012147619 A1 WO 2012147619A1 JP 2012060610 W JP2012060610 W JP 2012060610W WO 2012147619 A1 WO2012147619 A1 WO 2012147619A1
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Prior art keywords
formula
proanthocyanidin
compound represented
composition
blood glucose
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PCT/JP2012/060610
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English (en)
Japanese (ja)
Inventor
雅裕 勝川
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キッコーマン株式会社
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Priority to JP2013512309A priority Critical patent/JP5900896B2/ja
Publication of WO2012147619A1 publication Critical patent/WO2012147619A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a compound represented by formula (I) and a blood glucose level elevation inhibitor containing proanthocyanidin.
  • the present invention also relates to a composition for preventing or treating lifestyle-related diseases and diseases related thereto, which comprises the compound represented by the formula (I) and proanthocyanidin.
  • lifestyle-related diseases such as diabetes, hyperlipidemia, hypertension and obesity are rapidly increasing. These diseases tend to merge with each other, and the existence of insulin resistance is considered to be largely involved in their underlyings. Therefore, by preventing or treating diabetes, that is, by suppressing an increase in blood glucose level, it may be considered that it also leads to the prevention or treatment of other lifestyle-related diseases such as hyperlipidemia, hypertension, obesity and the like. it can.
  • the total number of diabetes patients due to insulin resistance and the number of persons considered to be a spare group is said to exceed 13 million in Japan, and the number is ever increasing.
  • Drugs such as thiazolidine derivatives are known as antidiabetic agents.
  • drugs such as thiazolidine derivatives are effective for insulin resistance, it is reported that they have the side effect of increasing body fat due to long-term use.
  • grape seed extract contains a large amount of antioxidants represented by polyphenols, and in particular contains a high amount of proanthocyanidin having a strong antioxidant capacity.
  • Proanthocyanidins have been found to control blood hemoglobin glycation rates to low values and to be effective in the prevention and treatment of the progression of various complications including diabetic cataract (see, for example, Patent Document 1) . It has also been reported that anti-atherogenic action was observed in the combined administration of proanthocyanidin and isoflavone (see, for example, Patent Document 2).
  • R 1 is a substituted or unsubstituted benzene ring A represented by the formula (II); R 2 is H; The inhibitor of blood glucose level elevation according to [1] or [2], which is a compound wherein is a single bond.
  • a pharmaceutical or food or drink comprising the blood sugar level increase inhibitor according to any one of [1] to [3].
  • a method for preventing or treating a lifestyle-related disease and a disease associated therewith comprising the step of administering a prophylactically or therapeutically effective amount of the compound represented by the above formula (I) and proanthocyanidin to a subject.
  • a method for the prophylaxis or treatment of diabetes and a disease associated therewith comprising the step of administering a prophylactically or therapeutically effective amount of the compound represented by the above formula (I) and proanthocyanidin to a subject.
  • the present invention relates to a compound represented by formula (I) and a blood glucose level elevation inhibitor containing proanthocyanidin.
  • the blood glucose level elevation inhibitor of the present invention may be a combination of compounds of natural origin.
  • by containing the compound represented by the formula (I) and proanthocyanidin it is more effective in that it is possible to provide an inhibitor of blood sugar level increase with less side effects of body fat increase. .
  • a composition for preventing or treating a lifestyle-related disease and a disease associated therewith which comprises the compound represented by the formula (I) and proanthocyanidin can be provided.
  • the composition for preventing or treating is a composition for treating or preventing diabetes.
  • the composition for the prevention or treatment may contain a combination of compounds of natural origin.
  • a composition for preventing or treating lifestyle-related diseases with less side effects of body fat increase and diseases related thereto is provided. It is more effective in that it can
  • Lifestyle-related diseases and diseases associated therewith include, for example, hyperglycemia and diseases associated with hyperglycemia such as obesity, hyperlipidemia and diabetes.
  • diabetes refers to chronic general metabolic disorders resulting from hyperglycemia or ketoacidosis, as well as long-term hyperglycemic condition or decreased glucose tolerance. Diabetes also includes both type 1 and type 2 (non-insulin dependent diabetes, or NIDDM) diseases.
  • composition of the present invention preferably contains the compound of formula (I) and proanthocyanidin in a prophylactically or therapeutically effective amount in the prevention or treatment of lifestyle diseases and diseases related thereto.
  • the prophylactically or therapeutically effective amount is the subject or disease or condition to be prevented or treated, weight and age of the subject, severity of the disease or condition, to the extent that the disease or condition can be prevented or treated. It will vary depending on the method of administration and the like, and can be easily determined by one skilled in the art.
  • the present invention provides a subject with a composition comprising a prophylactically or therapeutically effective amount of a compound represented by the formula (I) and proanthocyanidin to a subject to treat a lifestyle-related disease and a disease related thereto in the subject Including preventing or treating.
  • the composition can also be administered to the subject as a dietary supplement or as an additive to food.
  • the composition of the present invention which comprises the compound represented by the formula (I) and proanthocyanidin, is a composition comprising a mixture of the compound represented by the formula (I) and proanthocyanidin when administered to a subject.
  • the composition may be a combination of a compound represented by formula (I) and proanthocyanidin.
  • the present invention also relates to a method for suppressing elevated blood glucose levels, preferably with less side effects of increased body fat, by administering a compound of formula (I) and proanthocyanidins.
  • composition for preventing or treating a blood glucose level increase inhibitor containing a compound represented by the formula (I) and proanthocyanidin according to the present invention and a lifestyle-related disease and a disease related thereto (hereinafter simply referred to as “the composition of the present invention
  • the ratio of the compound represented by the formula (I) to proanthocyanidin is 1: 10,000 to 10000: 1, preferably 1: 1000 to 1000: 1, more preferably Is 1: 100 to 100: 1.
  • the compound represented by the formula (I) in the composition of the present invention has the following structure.
  • any one of R 1 and R 2 has the following formula (II): (In the formula, X 1 to X 5 are each independently H, OH or OMe) A substituted or unsubstituted benzene ring A represented by and the other is H or OH (preferably H); R 3 to R 6 are each independently H, OH or OMe; ----- is a single bond or a double bond.
  • X 1 is H;
  • X 2 is H or OH;
  • X 3 is H, OH or OMe;
  • X 4 is H;
  • X 5 is H or OMe.
  • R 1 is a substituted or unsubstituted benzene ring A represented by the formula (II) (in the formula (II), X 1 to X 5 are each independently H, OH or OMe); R 2 is H; R 3 to R 6 are each independently H, OH or OMe; ------ is a single bond; More preferably, in the above formula (I): R 3 is H or OH; R 4 is H; R 5 is OH; R 6 is H; In the above formula (II): X 1 is H; X 2 is H or OH, X 3 is H, OH or OMe; X 4 is H; X 5 is H or OMe.
  • Flavanones are coloring components often found in citrus, and examples thereof include naringenin, naringin, hesperidin, hesperetin, citronin, citronetin, liquiritin, liquiritigenin and the like.
  • the compound represented by the formula (I) is naringenin or hesperetin.
  • R 1 is a substituted benzene ring A represented by the formula (II) (wherein X 1 , X 2 , X 4 and X 5 are each H; X 3 is , OH); R 2 , R 4 and R 6 are each H; R 3 and R 5 are each OH;-----is a single bond .
  • R 1 is a substituted benzene ring A represented by the formula (II) (wherein X 1 , X 4 and X 5 are each H; X 2 is OH And X 3 is OMe); R 2 , R 4 and R 6 are each H; R 3 and R 5 are each OH; Is a compound that is
  • R 1 is H
  • R 2 is a substituted or unsubstituted benzene ring A represented by the formula (II);
  • R 3 to R 6 are each independently H, OH or OMe; ------ is a double bond; More preferably, in the above formula (I): R 3 is H or OH; R 4 is H or OMe; R 5 is OH; R 6 is H;
  • X 1 is H; X 2 is H; X 3 is OH or OMe; X 4 is H; X 5 is H.
  • Compounds having the structure (and glycosides thereof) are generally referred to generally as isoflavones.
  • the isoflavones are components which are often contained in legumes such as soybeans, and examples thereof include genistein, genistin, daidin, daidzein, glycitein, biochanin, formononetin and the like.
  • the compound represented by formula (I) is genistein.
  • R 2 is a substituted benzene ring A represented by the formula (II) (wherein X 1 , X 2 , X 4 and X 5 are each H; X 3 is , OH); R 1 , R 4 and R 6 are each H; R 3 and R 5 are each OH;----is a double bond is there.
  • R 1 is a substituted or unsubstituted benzene ring A represented by the formula (II);
  • R 2 is H;
  • R 3 to R 6 are each independently H, OH or OMe;
  • ------ is a double bond.
  • Compounds having the structure (and glycosides thereof) are generally referred to as flavones. Flavones are plant pigments found in various plants, and include, for example, abigenin, luteolin, tangeritin, diosmin, flavoxate and the like.
  • the composition for preventing or treating lifestyle-related diseases and diseases related thereto is preferably a compound represented by the above-mentioned formula (I) (wherein R 1 is a compound of the formula (II) is a substituted or unsubstituted benzene ring A; R 2 is H or OH (more preferably H); ----- is a single bond or a double bond (more Preferably, it contains a single bond) and proanthocyanidin.
  • formula (I) wherein R 1 is a compound of the formula (II) is a substituted or unsubstituted benzene ring A; R 2 is H or OH (more preferably H); ----- is a single bond or a double bond (more Preferably, it contains a single bond) and proanthocyanidin.
  • the compounds represented by formula (I) may be derivatives in which part of the structure is modified or modified.
  • Examples of the derivative of the compound represented by the formula (I) include physiologically acceptable salts, glycosides, esters, prodrugs or metabolites.
  • the physiologically acceptable salt of the compound represented by the formula (I) is not particularly limited, and, for example, alkali metal (sodium, potassium etc.) salts, alkaline earth metal (magnesium, calcium etc.) salts etc. These include alkali metal or alkaline earth metal hydroxides or carbonates, and base addition salts to which alkali metal alkoxides (sodium methoxide, potassium t-butoxide, etc.) are added.
  • the glycoside of the compound represented by the formula (I) is not particularly limited, and examples thereof include 6-carbon sugar or glucose of rhamnose, rutinose (glucose + rhamnose), apiose etc. (preferably, glucose or rutinose).
  • An OH group of a compound represented by the formula (I) is attached to an OH group of a sugar which is a five-carbon sugar or a derivative thereof (eg, a modified sugar subjected to acetylation, malonylation etc.) or a combination of two or more thereof Condensed O-glycosides can be mentioned.
  • Many of the compounds represented by formula (I) are known to occur naturally in the form of glycosides.
  • the glycoside of daidzein is soybean in
  • the glycoside of hesperitin is hesperidin
  • the glycoside of naringenin is naringin.
  • the prodrug of the compound represented by the formula (I) is not particularly limited as long as it is a compound which can be converted to the compound represented by the formula (I) after being administered to a living body, and the stability or For the purpose of improvement of absorbability, reduction of side effects, etc., compounds represented by the formula (I), which are made into a prodrug by a known method, can be mentioned.
  • the prode of the compound represented by the formula (I) It can be a drug.
  • it may be an ester.
  • the ester is also an ester corresponding to a prodrug, but is not particularly limited as long as it is a compound in which an acid and an alcohol hydroxyl group are simply bonded, and as the ester of the compound represented by formula (I), preferred is
  • a known acid not limited to a carboxylic acid ester, and a phosphoric acid ester, a nitric acid ester, a sulfuric acid ester and the like can also be mentioned).
  • the metabolite of the compound represented by the formula (I) is not particularly limited as long as it is a compound produced in the process of metabolism after administration of the compound represented by the formula (I) to a living body, It may be an intermediate product or an end product.
  • a compound produced from the compound represented by the formula (I) by the action of an in vivo enzyme, an enzyme produced by an in vivo microorganism or an enzyme produced by the microorganism itself can be mentioned.
  • equol is mentioned as a metabolite of daidzein
  • dihydroflavonol is mentioned as a metabolite of flavanone.
  • a commercial item may be used as a compound represented by Formula (I), and what was synthesize
  • the compound represented by the formula (I) is a compound contained in a natural product such as a plant, the compound represented by the formula (I) can be more conveniently obtained from those plant sources. If it is a metabolite of the compound represented by Formula (I), a metabolism related enzyme can be made to act on the compound represented by Formula (I), and it can also acquire.
  • naringenin is known to be present in grapefruit, peel of tomato, etc .; hesperetin is present in lemon and orange; genistein is present in leguminous plants such as soybeans; Can be extracted and obtained from such plant sources.
  • equol can be produced and obtained from isoflavone by the action of a specific enteric bacterium.
  • naringenin in the case of naringenin, it can be extracted from a tomato fruit origin containing tomato peel in the following manner.
  • an extract containing naringenin can be obtained by adding 5 to 20 times the amount of 50 to 90% ethanol to tomato fruit origin containing tomato peel and performing extraction at 40 to 80 ° C. for 1 to 5 hours. it can.
  • Purification of naringenin by subjecting this to purification with silica gel using an organic solvent such as ethyl acetate or n-hexane as an eluent or purification using ODS reverse phase resin using a water-acetonitrile solvent as an eluent it can.
  • Whether naringenin is contained in the obtained composition can be confirmed by a conventional method such as HPLC using a standard.
  • the tomato fruit origin used as a raw material will not be specifically limited if it contains a tomato peel.
  • the squeezed cake obtained in the process of obtaining squeezed juice of tomato fruit is generally discarded or used as livestock feed, but if this squeezed cake is used, waste raw materials can be effectively used and naringenin at a high concentration is obtained. Is preferable because it is possible to easily and efficiently obtain a composition containing
  • Tomato juice used as tomato juice, tomato puree, tomato paste, etc.
  • Tomato juice is obtained by washing and crushing tomato fruits according to a conventional method, followed by preheating, and then squeezing this. In the course of this squeezing, approximately 1 to 5% of the fruit develops as a squeezer.
  • the juju is mainly composed of a peel and a seed, and is rich in fibers such as water soluble dietary fiber such as pectin and insoluble dietary fiber such as cellulose and hemicellulose, as well as polyphenols Since it also remains, it can also be suitably used as a composition containing naringenin.
  • composition of the present invention is not limited to one including only the compound represented by the formula (I) purified as described above, but includes a crudely purified product of the compound represented by the formula (I) May be
  • the purified product or crude product thus obtained may be used as it is as the composition of the present invention, or may be added to the following pharmaceutical products, food and drink and the like.
  • the proanthocyanidin used in the present invention is a compound group in which condensed tannins present in various plant bodies, that is, flavan-3-ol or flavan-3,4-diol, are combined by polymerization as a constitutional unit, and they are acid-treated To produce anthocyanidins such as cyanidin, delphinidin, pelargonidin and the like. Types A and B exist depending on the mode of binding.
  • Proanthocyanidins include procyanidins, prodelphinidins, propellagonidins and the like which are polymers (dimers or more) of the above-mentioned constituent units. Further, proanthocyanidins include stereoisomers, glycosides, gallic acid esters, and various derivatives such as caffeic acid esters of the above compounds. In the present invention, proanthocyanidin can be used as proanthocyanidin of various molecular weights (degree of polymerization). Also, proanthocyanidin compositions fractionated according to molecular weight (degree of polymerization) can be used alone or in combination.
  • Proanthocyanidins can be obtained from plants or microorganisms by any extraction method, fermentation method, chemical or enzymatic synthesis method, etc. known to those skilled in the art.
  • proanthocyanidins may be extracts of grape seeds or peels, or may be commercial products.
  • proanthocyanidin derived from grape seed, trade name "Gravinol” (registered trademark, manufactured by Kikkoman Corporation), proanthocyanidin derived from apple fruit, trade name “Applephenone” (registered trademark, Asahi Beer Co., Ltd.) , Proanthocyanidin derived from the bark of seacoast pine, trade name “Pycogenol” (registered trademark, manufactured by Hoffer Research), “flavangenol” (registered trademark, manufactured by Toyo Shinyaku Co., Ltd.), and the like can be used.
  • Gramvinol registered trademark, manufactured by Kikkoman Corporation
  • Applephenone registered trademark, Asahi Beer Co., Ltd.
  • Proanthocyanidin derived from the bark of seacoast pine trade name “Pycogenol” (registered trademark, manufactured by Hoffer Research), “flavangenol” (registered trademark, manufactured by Toyo Shinyaku Co., Ltd.), and the like can be used
  • the composition of the present invention may contain 0.1 to 1,000 mg of the compound represented by the formula (I) and 0.1 to 1,000 mg of proanthocyanidin.
  • the composition of the present invention has a weight ratio of 1: 10000 to 10000: 1, preferably 1: 1000 to 1000: 1, more preferably 1: 100 to 100: 1.
  • a composition comprising a mixture of the compound of the present invention and proanthocyanidin, and further comprising 0.1 to 1,000 mg of the compound represented by the formula (I) and 0.1 to 1,000 mg of proanthocyanidin It is also good.
  • compositions according to the invention may comprise one or more additives.
  • composition of the present invention When the composition of the present invention is used as a pharmaceutical, pharmaceutically acceptable excipients can be added to make a pharmaceutical preparation.
  • Pharmaceutical preparations are not particularly limited, but external use such as tablets, capsules, granules, fine granules, powders, solutions, syrups, oral preparations such as chewables, troches, ointments, gels, creams, patches etc. It can be in the form of an agent, an injection, a sublingual agent, an inhalant, an eye drop, a suppository and the like.
  • the preferred dosage form is an oral preparation.
  • it may be a kit containing naringenin and proanthocyanidin as a pharmaceutical preparation.
  • compositions of the present invention include wetting agents, emulsifying agents, lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coatings, sweetening agents, flavoring agents, preservatives and antioxidants. It may be done.
  • antioxidants examples include (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogensulfate, sodium bisulfite, sodium sulfite etc., (2) ascorbyl palmitate, Oil-soluble antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc., and (3) citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol And metal chelating agents such as tartaric acid, phosphoric acid and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogensulfate, sodium bisulfite, sodium sulfite etc.
  • oil-soluble antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocophe
  • compositions suitable for oral administration include capsules, cachets, pills, tablets, lozenges, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil They may be in the form of liquid emulsions of the type, elixirs or syrups, these preparations containing defined amounts of naringenin and proanthocyanidin as active ingredients.
  • a pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate
  • starch lactose, sucrose, glucose, mannitol and Extenders such as silicic acid
  • carboxymethylcellulose alginates, gelatin, polyvinylpyrrolidone
  • binders such as sucrose and acacia
  • wetting agents such as glycerol
  • agar, calcium carbonate, potato Or disintegrants such as tapioca starch, alginic acid, certain silicates and sodium carbonate
  • dissolution retarders such as paraffin
  • absorption enhancers such as quaternary ammonium compounds
  • cetyl alcohol and Wetting agents such as glycerol monostearate, (9) kaolin and bentonite cake
  • Adsorbents such as chromatography, (10) talc, calcium stearate, solid polyethylene glycols, lubricating agents such as sodium lauryl
  • the pharmaceutical composition may contain excipients other than those described above, and in the case of capsules, tablets and pills, the pharmaceutical preparation may contain a buffer.
  • the solid composition may also be soft and hard gelatine capsules using fillers such as lactose or milk sugar as well as high molecular weight polyethylene glycol and the like.
  • the dose of the composition of the present invention can be appropriately set according to the target disease and condition, the degree of the disease, the age of the subject, body weight and the like.
  • the effective dose of the composition consisting of the mixture is in the range of 0.2 to 2,000 mg, preferably for example 0.4, in the mixture composition of the compound of the formula (I) and proanthocyanidins consumed with the food. It is approximately 200 mg / kg body weight.
  • the daily dose of the composition of the present invention taken at the beginning of the day is 1,000 mg.
  • the compositions of the present invention may be taken in divided doses to achieve a 1,000 mg daily dose.
  • concentration at which the composition is incorporated into the food product varies according to the type of food and drink and the amount of typical food and beverage.
  • the composition of the present invention may be added in an amount of 0.01 to 100 mg per mL of beverage and may be added in an amount of 0.01 to 100 mg per g of food.
  • the administration route of the composition of the present invention is not particularly limited, and it can be administered orally or parenterally, but can be conveniently administered orally.
  • the composition of the present invention can be blended into food and drink from the viewpoint of easy intake.
  • food and drink include supplements, food for specified health use, nutritive function food, health food, functional food, health supplements, ordinary food and drink, and the like.
  • the shape of the food and drink includes juice, soft drink, drink, liquid such as tea, biscuit, tablet, granular powder, powder, solid such as capsule, paste, jelly, semi-liquid such as soup, seasoning, dressing, etc. Can be mentioned.
  • These food and drink can be manufactured by adding the compound represented by the formula (I) and proanthocyanidin using any method known to those skilled in the art.
  • Foods and beverages can be used to prevent lifestyle-related diseases (eg, obesity, hyperglycemia, hyperlipidemia, diabetes, arteriosclerosis, etc.), to suppress blood sugar elevation, to improve lifestyle-related diseases, to promote lipid metabolism, to promote carbohydrate metabolism.
  • lifestyle-related diseases eg, obesity, hyperglycemia, hyperlipidemia, diabetes, arteriosclerosis, etc.
  • the food and drink may be labeled with an indication such as fat accumulation suppressing action, exercise endurance improving action, exercise alternative action and the like.
  • the food / beverage products which attached the display to the effect of having a body fat increase suppression effect may be sufficient.
  • the intake of food and drink can be appropriately adjusted depending on the use, for example, the compound represented by the formula (I) and proanthocyanidin in dry matter are each preferably 0.1 to 1000 mg / day, preferably Can be taken in amounts of 10 to 1000 mg / day.
  • the number of intakes is not particularly limited, it is preferably 1 to 3 times a day, and may be increased or decreased as needed.
  • the food and drink are preferably tomato processed food and drink, citrus processed food and drink, soy processed food and drink, and processed grape food.
  • tomato processed food and drink include tomato juice, tomato mix juice, tomato ketchup, tomato sauce, chili sauce, tomato juice drink, solid tomato, tomato puree, tomato paste, tomato soup and the like.
  • citrus processed food and drink include juice using citrus such as lemon, orange and grapefruit, juice mixed with citrus, solid citrus, jam containing citrus, puree, sauce and the like.
  • soy processed food and drink include soy milk, juice mixed with soy milk, solid soy, soup containing soy, sauce and the like.
  • grape processed food and drink examples include juice, jam, wine, grape seed oil and the like using grape seeds or peel as a raw material, as well as soups containing these, sauces, oil pickles and the like.
  • These tomatoes, citrus fruits, soybeans or grape processed food and drink are prepared by adding the compound represented by the formula (I) and proanthocyanidin according to a method (recipe, etc.) of ordinary tomato, citrus, soybean or grape processed food or drink
  • a method pe, etc.
  • the food and drink may be prepared by adding proanthocyanidin.
  • the food or drink may be in the form of a beverage or a food, such as cookies, chocolate cake with nuts, crackers, grain bars such as bleach bar, energy bar, corn flakes and cakes. It may be a baked food, fruit juice, vegetable drink, carbonated drink, sport drink, coffee or tea drink.
  • Example 1 (Effect of simultaneous intake of proanthocyanidin and naringenin on suppression of blood sugar elevation) Using 41 KKAy (5 weeks old) male (produced by CLEA Japan, Inc.) males (produced by CLEA Japan, Inc.), it was confirmed that naringenin and proanthocyanidin have an action to suppress the increase in blood glucose level. After preliminary breeding of 5-week-old male mice for 1 week with feed AIN-93G (Oriental Yeast Co., Ltd.), body weight, blood glucose level and HbA1c are measured, and grouping is performed so that blood glucose and body weight do not differ between groups did.
  • AIN-93G Oriental Yeast Co., Ltd.
  • Grouping was performed as follows, with one group consisting of nine animals: (1) Normal food group (control group); (2) Actos (registered trademark Takeda Pharmaceutical Co., Ltd., Actos tablet containing 15 mg / tablet of pioglitazone was crushed and mixed.) 0.03% feeding group; (3) Proanthocyanidin water (GSE water: Gravinol SL (registered trademark, manufactured by Kikkoman Foods Co., Ltd.): dissolved in water to a concentration of 300 mg / 350 mL as a proanthocyanidin concentration) Free intake group; (4) Naringenin (Aldrich) 1% feeding group; and (5) proanthocyanidin water free intake + naringenin 1% feeding group; Total 5 groups (9 animals in 1, 3, 4, 5 groups, 5 animals in 2 groups).
  • Proanthocyanidin was free intake by drinking water.
  • the daily water consumption of one KKAy mouse in the control group is approximately 11 to 17 g, whereas the daily water consumption of one KKAy mouse in the proanthocyanidin water free intake + naringenin 1% feeding group is approximately 5 to It was 7 g and the intake of proanthocyanidin was about 5 to 7 mg (Table 1).
  • the proanthocyanidin water free intake + naringenin 1% mixed feed group a slight decrease in food consumption was observed during the first week, so from 1 week after the start of the test, proanthocyanidin water free intake for all other feeding amounts + Same as Naringenin 1% feeding group.
  • the feed intake of proanthocyanidin water free intake + naringenin 1% mixed feed group was about 5 g, and the intake of naringenin was about 5 mg.
  • Water consumption (g) (indicated by mean ⁇ standard error) * Indicates a significant difference of 5% in the risk factor according to the Fisher's PLSD method of each group to the control group (the same applies to the following).
  • the test is conducted for 4 weeks (28 days), body weight, food intake and water intake are measured, and blood sugar level is occasionally measured using Antsense III (Horiba Mfg. Co., Ltd.) and HbA1c is DCA 2000+ (Siemens). It was measured. After the test, fat (subcutaneous, mesentery, perirenal, epididymis), gastrocnemius and liver were removed, and the weight of adipose tissue was measured. As for body weight of KKAy mice, a large increase was observed in Actos 0.03% feeding group (Table 2). On the other hand, the weight gain of proanthocyanidin water free intake + naringenin 1% mixed feeding group was smaller than that of actos 0.03% mixed feeding group.
  • HbA1c (hemoglobin A1c) is a type of glycohemoglobin.
  • the amount of HbA1c in blood is proportional to the blood glucose level from the time of red blood cell production to the present, and is also used as a diagnostic standard of diabetes.
  • Example 2 (Effect of simultaneous intake of proanthocyanidin and hesperetin on suppression of blood sugar elevation) Using 40 KKAy mice (10 weeks old) and 40 males (manufactured by CLEA Japan, Inc.), it was confirmed that hesperetin and proanthocyanidin have a suppressive effect on the blood sugar level increase.
  • the body weight and blood glucose level of 10-week-old KKAy mice were measured, and the blood glucose and body weight were divided into groups so that there was no difference between the groups.
  • Grouping was conducted as follows, with one group consisting of 10 animals: (1) Control group (0.5% CMCNa solution gavage group); (2) GSE 10 mg / day gavage group (equivalent to GSE intake in Example 1 (per body weight)); (3) Hesperetin (Aldrich) 52 mg / day gavage oral administration group (equivalent to naringenin intake in Example 1 (per body weight)); and (4) GSE 10 mg / day + hesperetin 52 mg / day gavage oral administration group; A total of 4 groups. Each sample of groups 2 to 4 was dissolved in 0.5% CMCNa (sodium carboxymethylcellulose) solution, and 0.4 mL of each group was orally administered orally.
  • CMCNa sodium carboxymethylcellulose
  • the GSE or hesperetin alone intake group did not show a drop in blood glucose level as compared to the control group, but the blood glucose level drop was observed in the GSE and hesperetin coadministration group (Table 6).
  • Example 3 (Effect of simultaneous intake of proanthocyanidin and genistein on suppression of blood sugar elevation) Using 40 KKAy mice (13 weeks old), 40 males (manufactured by CLEA Japan, Inc.), the effect of genistein and proanthocyanidin on suppressing blood sugar level elevation was confirmed. The body weight and blood glucose level of 13-week-old KKAy mice were measured, and the blood glucose and body weight were divided into groups so that there was no difference between the groups.
  • Grouping was conducted as follows, with one group consisting of 10 animals: (1) Control group (0.5% CMCNa solution gavage group); (2) GSE 10 mg / day gavage group (equivalent to GSE intake in Example 1 (per body weight)); (3) Genistein (Funakoshi Co., Ltd.) 52 mg / day oral gavage group (equivalent to naringenin intake in Example 1 (per body weight)); and (4) GSE 10 mg / day + genistein 52 mg / day oral gavage group; A total of 4 groups. Each sample of groups 2 to 4 was dissolved in 0.5% CMCNa solution, and 0.4 mL of each group was orally administered orally.
  • Example 4 Production of processed tomato food and drink containing naringenin and proanthocyanidin
  • the production example of a processed tomato food or beverage using naringenin and proanthocyanidin as part of the raw material is shown below.
  • Tomato juice The method for producing season-packed tomato juice includes tomato washing, sorting, crushing, heating, squeezing, blending, degassing, sterilizing, filling, cooling and boxing steps, and the tomato juice squeezed in this blending step
  • naringenin and proanthocyanidin are added and formulated, and salt is added only in the case of salted, mixed with nitrogen gas and degassed under reduced pressure to make the dissolved oxygen concentration 3 ppm or less Heat-sterilize at 121 ° C. for about 1 minute, cool to 90 ° C., and fill in cans.
  • the tomato concentrate in the opening step, is opened and then diluted with water to a prescribed non-salt soluble solid content (4.5 or more). After that, naringenin and proanthocyanidin are added and prepared, and it is manufactured through the steps of degassing, sterilizing, filling, cooling and boxing.
  • Vegetable mix juice Various tomato juice, naringenin with composition of Table 10 to tomato juice obtained by water dilution of squeezed tomato juice or tomato concentrate into prescribed salt-free soluble solid content (4.5 or more) And proanthocyanidin is added and prepared, and it is manufactured through the steps of degassing, sterilizing, filling, cooling and boxing.
  • Tomato source All raw materials shown in Table 11 are mixed, mixed with nitrogen gas and degassed under reduced pressure to reduce dissolved oxygen concentration to 3 ppm or less, then filled in No. 2 can and retort sterilized at 110 ° C for 30 minutes Do.
  • a production example of a processed food or beverage using a compound represented by the formula (I) other than naringenin and proanthocyanidin as a part of the raw material can be produced according to the same procedure as in Example 4 above.

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Abstract

La présente invention concerne un inhibiteur d'augmentation du niveau de glycémie. La présente invention concerne également une composition pour la prévention ou le traitement de maladies liées au mode de vie et de troubles associés. La présente invention concerne un inhibiteur d'augmentation du niveau de glycémie comprenant un composé représenté par la formule (I), ainsi qu'une proanthocyanidine. La présente invention concerne également une composition pour la prévention ou le traitement de maladies liées au mode de vie et de troubles associés, la composition contenant un composé représenté par la formule (I), ainsi qu'une proanthocyanidine.
PCT/JP2012/060610 2011-04-27 2012-04-19 Inhibiteur d'augmentation du niveau de glycémie WO2012147619A1 (fr)

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JP7296623B2 (ja) * 2019-07-23 2023-06-23 株式会社ファイン α－アミラーゼ活性阻害剤及びα－アミラーゼ活性阻害剤の製造方法

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JP2021167281A (ja) * 2020-04-09 2021-10-21 カゴメ株式会社 血糖値上昇抑制用組成物

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